1. Field of the Invention
The present invention relates to a class of novel compounds useful in the treatment of a variety of diseases that involve undesirable inflammatory or hypersensitivity responses in diverse animal tissues. Approaches to the treatment of these responses have been as varied as the tissues in which such responses take place, and include the administration of antihistamines, analgesics such as aspirin, topical coal tar as well as others.
A more recent approach to the moderation of inflammatory and hypersensitivity responses has focused on blocking the action of arachidonic acid metabolites (including the prostaglandins), lipoxygenases and the leukotrienes. The leukotrienes (LT) metabolites are formed by oxygenation of a lipoxygenase (5-hydroperoxy-tetraenoic acid (5-HPETE)) which is formed by the specific oxygenation of the C-5 position of arachidonic acid. The first leukotriene formed in the metabolic pathway is the unstable epoxide intermediate leukotriene A.sub.4 (LTA.sub.4) which is the precursor to the family of peptido-leukotrienes, the first in the pathway being LTC.sub.4 which is formed by glutathione addition. LTC.sub.4 is transformed subsequently into LTD.sub.4 and LTE.sub.4 by successive elimination of a glutamyl and glycine residue. The peptido-leukotrienes primarily act on smooth muscle and other cells having contractile capacity, as well as playing a key role in hypersensitivity reactions. In addition, the peptido-leukotrienes are spasmogens, increase vascular permeability, activate airway smooth muscle, stimulate mucous secretion and are involved with the pathogenesis of certain inflammatory diseases such as bronchitis, ectopic and atopic eczema and psoriasis. Leukotrienes appear to be involved in the pathogenesis of asthma such as allergic pulmonary disorders of asthma, hay fever and allergic rhinitis. In addition, LTC.sub.4, LTD.sub.4 and LTE.sub.4 may also decrease blood pressure by an action on the heart, because they reduce myocardial contractility and coronary blood flow.
Another family of leukotrienes, LTB.sub.4, is derived from LTA.sub.4 by hydrolase-catalyzed addition of water. This 5, 12-dihydroxy derivative causes adhesion and chemotactic movement of leukocytes, stimulates aggregation, enzyme release and generation of superoxide in neutrophils. Additionally, LTB4 is a potent chemotactic and chemokinetic agent for eosinophils, macrophages and monocytes, stimulates suppressor T lymphocytes and enhances natural cytotoxic cell activity. LTB.sub.4 is also a potent (indirect) bronchoconstrictor but in contrast to the peptido-leukotrienes C.sub.4, D.sub.4 and E.sub.4 does not appreciably stimulate mucous production and induce edema of the airways by increasing vascular permeability.
2. Reported Developments
It has been suggested that compounds antagonizing LTB.sub.4 activity may be valuable in the treatment of inflammatory diseases caused by tissue degrading enzymes and reactive chemicals liberated by tissue-infiltrating and aggregating polymorphonuclear leukocytes. Such disease states include inflammatory bowel disease, reperfusion injury, chronic lung diseases, various arthritic conditions, inflammatory conditions associated with asthma (such as late phase hypersensitivity) and psoriasis.
The literature reports a variety of compounds exhibiting leukotriene B.sub.4 antagonist activity. These include compounds having chemical structures mimicking leukotriene structures such as Sumitomo's SM 9064, UpJohn's U-75360 and U-75302 and Ciba Geigy's CGS 23113. Other compounds, some of which include monocyclic ring structures and which are disclosed in EP 276064, EP 276065 and EP 292977, are reported to exhibit both LTD.sub.4 and LTB.sub.4 antagonist properties.
The present invention is directed to a class of novel bicyclic ring containing compounds which exhibit selective LTB.sub.4 antagonist activity.